Abnormal expression of homeobox genes and transthyretin in C9ORF72 expansion carriers

Nicole A. Finch, Xue Wang, Matthew C. Baker, Michael G. Heckman, Tania F. Gendron, Kevin F. Bieniek, Joanne Wuu, Mariely Dejesus-Hernandez, Patricia H. Brown, Jeannie Chew, Karen R. Jansen-West, Lillian M. Daughrity, Alexandra M. Nicholson, Melissa E. Murray, Keith A. Josephs, Joseph E. Parisi, David S. Knopman, Ronald C. Petersen, Leonard Petrucelli, Bradley F. BoeveNeill R. Graff-Radford, Yan W. Asmann, Dennis W. Dickson, Michael G Benatar, Robert Bowser, Kevin B. Boylan, Rosa Rademakers, Marka Van Blitterswijk

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Objective: We performed a genome-wide brain expression study to reveal the underpinnings of diseases linked to a repeat expansion in chromosome 9 open reading frame 72 (C9ORF72). Methods: The genome-wide expression profile was investigated in brain tissue obtained from C9ORF72 expansion carriers (n = 32), patients without this expansion (n = 30), and controls (n = 20). Using quantitative real-time PCR, findings were confirmed in our entire pathologic cohort of expansion carriers (n = 56) as well as nonexpansion carriers (n = 31) and controls (n = 20). Results: Our findings were most profound in the cerebellum, where we identified 40 differentially expressed genes, when comparing expansion carriers to patients without this expansion, including 22 genes that have a homeobox (e.g., HOX genes) and/or are located within the HOX gene cluster (top hit: homeobox A5 [HOXA5]). In addition to the upregulation of multiple homeobox genes that play a vital role in neuronal development, we noticed an upregulation of transthyretin (TTR), an extracellular protein that is thought to be involved in neuroprotection. Pathway analysis aligned with these findings and revealed enrichment for gene ontology processes involved in (anatomic) development (e.g., organ morphogenesis). Additional analyses uncovered that HOXA5 and TTR levels are associated with C9ORF72 variant 2 levels as well as with intron-containing transcript levels, and thus, disease-related changes in those transcripts may have triggered the upregulation of HOXA5 and TTR. Conclusions: In conclusion, our identification of genes involved in developmental processes and neuroprotection sheds light on potential compensatory mechanisms influencing the occurrence, presentation, and/or progression of C9ORF72-related diseases.

Original languageEnglish (US)
JournalNeurology: Genetics
Volume3
Issue number4
DOIs
StatePublished - Jan 1 2017

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Chromosomes, Human, Pair 9
Prealbumin
Homeobox Genes
Open Reading Frames
Up-Regulation
Genes
Genome
Gene Ontology
Brain
Multigene Family
Morphogenesis
Introns
Cerebellum
Real-Time Polymerase Chain Reaction
Proteins

ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)

Cite this

Finch, N. A., Wang, X., Baker, M. C., Heckman, M. G., Gendron, T. F., Bieniek, K. F., ... Van Blitterswijk, M. (2017). Abnormal expression of homeobox genes and transthyretin in C9ORF72 expansion carriers. Neurology: Genetics, 3(4). https://doi.org/10.1212/NXG.0000000000000161

Abnormal expression of homeobox genes and transthyretin in C9ORF72 expansion carriers. / Finch, Nicole A.; Wang, Xue; Baker, Matthew C.; Heckman, Michael G.; Gendron, Tania F.; Bieniek, Kevin F.; Wuu, Joanne; Dejesus-Hernandez, Mariely; Brown, Patricia H.; Chew, Jeannie; Jansen-West, Karen R.; Daughrity, Lillian M.; Nicholson, Alexandra M.; Murray, Melissa E.; Josephs, Keith A.; Parisi, Joseph E.; Knopman, David S.; Petersen, Ronald C.; Petrucelli, Leonard; Boeve, Bradley F.; Graff-Radford, Neill R.; Asmann, Yan W.; Dickson, Dennis W.; Benatar, Michael G; Bowser, Robert; Boylan, Kevin B.; Rademakers, Rosa; Van Blitterswijk, Marka.

In: Neurology: Genetics, Vol. 3, No. 4, 01.01.2017.

Research output: Contribution to journalArticle

Finch, NA, Wang, X, Baker, MC, Heckman, MG, Gendron, TF, Bieniek, KF, Wuu, J, Dejesus-Hernandez, M, Brown, PH, Chew, J, Jansen-West, KR, Daughrity, LM, Nicholson, AM, Murray, ME, Josephs, KA, Parisi, JE, Knopman, DS, Petersen, RC, Petrucelli, L, Boeve, BF, Graff-Radford, NR, Asmann, YW, Dickson, DW, Benatar, MG, Bowser, R, Boylan, KB, Rademakers, R & Van Blitterswijk, M 2017, 'Abnormal expression of homeobox genes and transthyretin in C9ORF72 expansion carriers', Neurology: Genetics, vol. 3, no. 4. https://doi.org/10.1212/NXG.0000000000000161
Finch, Nicole A. ; Wang, Xue ; Baker, Matthew C. ; Heckman, Michael G. ; Gendron, Tania F. ; Bieniek, Kevin F. ; Wuu, Joanne ; Dejesus-Hernandez, Mariely ; Brown, Patricia H. ; Chew, Jeannie ; Jansen-West, Karen R. ; Daughrity, Lillian M. ; Nicholson, Alexandra M. ; Murray, Melissa E. ; Josephs, Keith A. ; Parisi, Joseph E. ; Knopman, David S. ; Petersen, Ronald C. ; Petrucelli, Leonard ; Boeve, Bradley F. ; Graff-Radford, Neill R. ; Asmann, Yan W. ; Dickson, Dennis W. ; Benatar, Michael G ; Bowser, Robert ; Boylan, Kevin B. ; Rademakers, Rosa ; Van Blitterswijk, Marka. / Abnormal expression of homeobox genes and transthyretin in C9ORF72 expansion carriers. In: Neurology: Genetics. 2017 ; Vol. 3, No. 4.
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T1 - Abnormal expression of homeobox genes and transthyretin in C9ORF72 expansion carriers

AU - Finch, Nicole A.

AU - Wang, Xue

AU - Baker, Matthew C.

AU - Heckman, Michael G.

AU - Gendron, Tania F.

AU - Bieniek, Kevin F.

AU - Wuu, Joanne

AU - Dejesus-Hernandez, Mariely

AU - Brown, Patricia H.

AU - Chew, Jeannie

AU - Jansen-West, Karen R.

AU - Daughrity, Lillian M.

AU - Nicholson, Alexandra M.

AU - Murray, Melissa E.

AU - Josephs, Keith A.

AU - Parisi, Joseph E.

AU - Knopman, David S.

AU - Petersen, Ronald C.

AU - Petrucelli, Leonard

AU - Boeve, Bradley F.

AU - Graff-Radford, Neill R.

AU - Asmann, Yan W.

AU - Dickson, Dennis W.

AU - Benatar, Michael G

AU - Bowser, Robert

AU - Boylan, Kevin B.

AU - Rademakers, Rosa

AU - Van Blitterswijk, Marka

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N2 - Objective: We performed a genome-wide brain expression study to reveal the underpinnings of diseases linked to a repeat expansion in chromosome 9 open reading frame 72 (C9ORF72). Methods: The genome-wide expression profile was investigated in brain tissue obtained from C9ORF72 expansion carriers (n = 32), patients without this expansion (n = 30), and controls (n = 20). Using quantitative real-time PCR, findings were confirmed in our entire pathologic cohort of expansion carriers (n = 56) as well as nonexpansion carriers (n = 31) and controls (n = 20). Results: Our findings were most profound in the cerebellum, where we identified 40 differentially expressed genes, when comparing expansion carriers to patients without this expansion, including 22 genes that have a homeobox (e.g., HOX genes) and/or are located within the HOX gene cluster (top hit: homeobox A5 [HOXA5]). In addition to the upregulation of multiple homeobox genes that play a vital role in neuronal development, we noticed an upregulation of transthyretin (TTR), an extracellular protein that is thought to be involved in neuroprotection. Pathway analysis aligned with these findings and revealed enrichment for gene ontology processes involved in (anatomic) development (e.g., organ morphogenesis). Additional analyses uncovered that HOXA5 and TTR levels are associated with C9ORF72 variant 2 levels as well as with intron-containing transcript levels, and thus, disease-related changes in those transcripts may have triggered the upregulation of HOXA5 and TTR. Conclusions: In conclusion, our identification of genes involved in developmental processes and neuroprotection sheds light on potential compensatory mechanisms influencing the occurrence, presentation, and/or progression of C9ORF72-related diseases.

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